The process of this invention allows the economical solventfree synthesis of ethereally-substituted monosaccharides such as amiprilose, 1,2-O-isopropylidene-3-O-3'-(N',N'-dimethylamino-n-propyl)-.alpha.,D-gluco furanose and its' hydrochloric acid salt (amiprilose HCl).
Monosaccharides have been previously reported to have immunomodulatory activity, especially in infectious disease models. See Muchmore A. V., et al., Immunobiology 1981; 158:191-206; Rasanen L., Cell Immunol 1981; 58:19-28; Brunda M. J., et al., Int J Cancer 1983; 31:373-9; and Nencioni L., et al., Infect Immun 1985; 47:534-9. Several other glucofuranosides have been described as having potent anti-inflammatory properties and low toxicity. See Tannenbaum J., et al., Prostaglandins 1979; 17:337-50; Goi A., et al., Arzneimittelforschung 1979; 29:986-90; Jaques R., Pharmacology 1977; 15:445-60; Riesterer L., et al., Pharmacology 1970; 3:243-51; Jaques R., Pharmacology 1970; 4:193-202; Kuzuna S. et al., Yakuri to Chiryo August 1974; 2:997-1010; Bianchi C., Agents Actions 1981; 11:750-61; and Di Rosa M., Arch Int Pharmacodyn Ther 1968; 173:162-72. Ethereally-substituted monosaccharides and the therapeutic activity thereof are described in U.S. Pat. Nos. Re. 30,354 and Re 30,379; the disclosure of which are incorporated herein by reference.
The ethereally-substituted monosaccharide amiprilose has been reported to have anti-inflammatory properties in animal models predictive for anti-rheumatic effects in humans, including adjuvant arthritis, experimental monoarticular arthritis, and carageenan footpad edema See Gordon P., Inflammation, Mechanisms and Treatment, Willoughby D. A, Giroud J. P, eds., Baltimore: University Park Press; 1980:169-80. Other preliminary studies have suggested that amiprilose has anti-rheumatic effects in a type II collagen arthritis model and antiproliferative properties in cultured synoviocytes See Kieval R. I., et al., Arthritis Rheum 1988; 31:71N. The drug has also been reported to exhibit immunomodulatory properties, including macrophase stimulating effects. Morrison C. J., et al., Antimicrob Agents Chemmother 1984; 26:74-7; Hadden J. W., Cancer Treat Rep 1978; 62:1981-5; and Hadden J. W., et al., Int J Immunopharmacol 1979; 1:17-27. Amiprilose has also shown effects on circulating T8 lumphocytes in rheumatoid arthritic patients Weinblatt M. E, et al., J Rheumatol 1987; 14:859-60. Recently, patients treated with amiprilose have shown sequential decreases in serum interleukin-2 receptor levels that correlated with improvement in clinical measures of disease activity suggesting the possibility that amiprilose may diminish T-cell activation in patients responsive to the drug. Campen (D. H., et al., Arthritis Rheum. 1983; 31:1358-64. Most recently, Amiprilose HCl has been shown to be effective in the treatment of rheumatoid arthritis. Riskin W. G., et al. Ann. Int. Med. 1989; 111:455-465.
According to the method of U.S. Pat. No. 2,715,121, the synthesis of ethereally-substituted monosaccharides involves the reaction of a monosaccharide derivative which is blocked with one or more organo groups in the hydroxyl group positions adjacent to the desired position to be substituted. The blocked monosaccharide can be dissolved in an organic solvent such as dioxane, tetrahydrofuran or benzene and is reacted with a halogenated organo amino compound having the desired carbon chain length and configuration in the presence of a base such as sodium hydroxide. After the reaction is complete, selective removal of one or more blocking groups may be accomplished by hydrolysis under specific conditions.
With the above method, amiprilose HCl is prepared by first reacting a mixture of a 1,2:5,6-di-O-isopropylidene-.alpha.,D-glucofuranose (DAG), a hydrochloric acid salt of chloro-dimethyl aminopropane, and sodium hydroxide in dioxane at reflux for at least 9 to 11 hours to yield 1,2:5,6-Di-O-isopropylidine-3-O-3-(N'N'-dimethylamino-n-propyl)-.alpha.,D- glucofuranose. The total time taken to produce one batch of the diacetal blocked hexose ether in this first step from initial preparation of the reaction through isolation of the final product is about 50 hours. If the product is then hydrolyzed in aqueous environment to yield the desired amiprilose HCl, an additional 70 hours is required. Thus, the total time required for the overall synthesis is approximately 120 hours.
The process of U.S. Pat. No. 2,715,121 suffers from numerous disadvantages. First, a significant amount of time is required to synthesize and workup any desired product. Second, the process uses dioxane as a solvent which is toxic in nature and requires a special permit to use it in chemical plants. Third, hydrochloric acid salts of amino substituted alkylhalides, such as chloro-dimethylaminopropane hydrochloride (DMCP HCl), used in the synthesis of amiprilose, are significantly more expensive than the corresponding free base. Finally, the prior art process requires the disposal of expensive dioxane-containing waste which costs about $1.50 to $3.50 per liter.
The selective hydrolysis step also adds a significantly amount of time to the prior art process. The hydrolysis is generally carried out in refluxing solvent for approximately 2-4 hours. The aqueous hydrolysis medium requires pH adjustment which results in the production of mineral salts such as NaCl which precipitate out along with the amiprilose HCl and contaminate the product. The process often requires a series of steps where the mother liquor is concentrated and the precipitated product collected in order to obtain a satisfactory yield. Additionally, the product often requires a milling step to form a powder prior to pharmaceutical use.
Copending U.S. patent application Ser. No. 07/433,460, filed Oct. 1, 1990, now abandoned and commonly assigned to Greenwich Pharmaceuticals, Inc., discloses a solid phase Williamson's synthesis of diacetal blocked cyclic hexose ethers. The method comprises the steps of blending together, in the solid phase, a partially blocked acetal of a hexose sugar which is unblocked at one hydroxyl position of the hexose and an excess of anhydrous sodium hydroxide. The blended materials are reacted at a temperature and for a time sufficient to form water and a hexose sodium salt at the unblocked sugar position. Substantially all the water formed by the reaction is removed. The remaining blend of the hexose sodium salt product and unreacted, excess sodium hydroxide is mixed with an alkyl halide or substituted alkyl halide such that the hexose sodium salt condenses with the alkyl halide or substituted alkyl halide. The condensation reaction is conducted at a temperature sufficient to produce the ethereally-substituted hexose monosaccharide and a sodium halide. Finally, the sodium halide is removed to yield a purified ethereally-substituted hexose monosaccharide. The product may then undergo selective hydrolysis to remove the blocking groups.